Neuroinflammation as driving force for axonal regeneration in the adult mouse visual system: MMP2 as a possible modulator

Neurodegenerative disorders such as Alzheimer's (AD), Parkinson's (PD), and Huntington's disease, multiple sclerosis (MS), glaucoma, etc., represent a growing social and economic problem. This irreversible diseases usually occur later in life and affect an increasing number of people in our the aging society. Neurotrauma or degeneration drastically diminishes the quality of life and leads to severe impairments, largely because the central nervous system (CNS) in adult mammals has only a limited capacity to replace lost neurons (de novo neurogenesis), or - the focus of this study - to repair damaged axons (axonal regeneration) [1-4]. Indeed, once mammals surpass the postnatal phase, they loose their regenerative potential in the CNS due to the low intrinsic growth capacity of their neurons, the presence of extrinsic inhibitors and the loss of neurotrophic support [5-9]. Restoration of neuronal function after damage to the CNS involves effectuating neuroprotection, inducing axonal regeneration and/or de novo neurogenesis, stimulating correct axonal navigation, and reinnervation of the targets in the brain [10]. Despite decades of research efforts, full recovery after CNS injury or disease continues to be a challenge [4]. Thorough investigation of the mechanisms that contribute to successful axonal regeneration therefore remains essential, and can provide new insights in the development of strategies for functional recovery of neuronal projections in the CNS of adult mammals [5-7,9,11,12]. Since several years, neuroinflammation has been suggested as a mechanism that can stimulate the regeneration capacity of the CNS [13-15]. Where the inflammatory response was seen as a harmful process in the past, it is increasingly clear that inflammatory cells actually contribute to CNS repair by their positive impact on - among other things - axonal regeneration [13,16-18]. Yet, little is known about how inflammation may contribute to successful axonal regeneration in the CNS. Therefore, the overall aim of this project is to unravel the cellular and molecular mechanisms by which inflammation modulates axonal regeneration. In this researchproject, we will investigate axonal regeneration in the optic nerve. Indeed, the retinofugale system is a powerful model for studying axonal regeneration and identifying the underlying molecules and signaling pathways. It has already contributed significantly to the current understanding of the multifactorial causes that underlie the failure of axonal regeneration in the CNS of adult mammals. More specifically, we will use a validated inflammatory regenerative optic nerve crush (RONC) model in the mouse, which induces axonal regeneration, via controlled ocular inflammation. Based on an innovative comparative quantitative proteomics, we will identify novel molecules and map the signaling pathways, which link controlled inflammation to axonal regeneration. On the other hand, we will also build on earlier findings from the host lab, which suggest that matrix metalloproteinase-2 (MMP-2) is a key player during the initiation of axonuitgroei, possibly through effects on inflammation, as well as during axonelongation. In summary, the investigation of axonal regeneration is a challenge, but is essential for promoting CNS recovery and the fight for healthy aging. In this study we focus on the role of the innate immune system during axonal regeneration, and we are systematically searching for factors that link the natural process of inflammation to successful regeneration.status: publishe